Eiji Tayama,* Ryota Sato, Motoshi Ito, Hajime Iwamoto, and Eietsu Hasegawa

Transcription

1 HETEROCYCLES, Vol., No.,, pp. -. The Japan Institute of Heterocyclic Chemistry Received,, Accepted,, Published online,. DOI: /COM- (Please do not delete.) A UNIQUE AND SIMPLE PREPARATIVE METHOD FOR -ARYL PIPECOLINIC ACID ESTERS VIA BASE-INDUCED SOMMELET HAUSER REARRANGEMENT Eiji Tayama,* Ryota Sato, Motoshi Ito, Hajime Iwamoto, and Eietsu Hasegawa Department of Chemistry, Faculty of Science, Niigata University, Niigata Japan Abstract A unique and simple preparative method for N-cyano- -aryl pipecolinic acid esters via base-induced Sommelet Hauser rearrangement, the von Broun reaction, and intramolecular -alkylation is reported. The removal of the N-cyano substituent was achieved by hydrogenation and hydride reduction. INTRODUCTION Six-membered cyclic -amino acid derivatives, such as pipecolinic acid, occur in numerous biologically important natural products and are pharmacologically interesting as building blocks for synthetic drugs. 1 Various synthetic methods, including asymmetric synthesis, have been reported; however, preparative methods for -substituted (quaternary) pipecolinic acids are limited, 2 especially for -aryl derivatives 3,4 because of the difficulty of C C bonds formation between aromatic (sp 2 ) and piperidinyl (sp 3 ) carbons. Previously, we reported the base-induced Sommelet Hauser (S H) rearrangement 5 of N-benzylic amino acid-derived ammonium ylides, which enables the formation of C(sp 2 ) C(sp 3 ) bonds under mild conditions and affords various types of -aryl amino acids such as -arylproline, -arylglycine, and -arylalanine derivatives. 6,9 In the course of our study of the S H rearrangement, we carried out a reaction involving N-benzylpipecolinic acid-derived tetraalkylammonium salt 1 to prepare -(o-tolyl)pipecolinic acid ester 2 to expand the synthetic scope of the rearrangement. However, our attempt failed because the cooperative [1,2] Stevens rearrangement proceeded to afford exclusively -benzylated 3 (eq. 1). 7 Recently, we reported that the von Broun reaction 8 of methyl 2-phenyl-2-pyrrolidinylacetate 5a gave the corresponding ring-opening product 6a in a 94% yield (eq. 2). 9 Substrate 5a appears to be a model S H rearrangement product, and product 6a may be a good synthetic intermediate for the synthesis of -aryl pipecolinic acid derivatives because only a simple

2 intramolecular -alkylation (cyclization) would be required. In fact, the previous synthetic route to -aryl pipecolinic acids mainly involves intramolecular -alkylation (cyclization) of N- or -(4-halobutyl)- -arylglycine derivatives. 3 Thus, we started to investigate a new synthetic route for synthetically valuable -aryl pipecolinic acid esters 7 from easily accessible tetraalkylammonium salts 4 via S H rearrangement, the von Broun reaction, and intramolecular -alkylation (eq. 3). RESULTS AND DISCUSSION First, we examined the cyclization of 6a by treatment with 1.1 equivalents of LDA (Scheme 1). The desired N-cyano- -aryl pipecolinic acid ester 7a was obtained in a 91% yield. Scheme 1 With this reaction in hand, we prepared N-benzylglycine-derived tetraalkylammonium salt 4b and analyzed the reactions to investigate the possibility of obtaining -aryl pipecolinic acid derivatives 7 from 4 via S H rearrangement (Scheme 2). The corresponding o-tolyl derivative 6b was obtained via the S

3 H rearrangement of 4b (68%) and the von Broun reaction of 5b (91%). However, 6b did not cyclize to 7b after treatment with LDA. The addition of HMPA did not result in any improvement. Thus, we used potassium bis(trimethylsilyl)amide (KHMDS) as a base to generate the reactive potassium enolate. The desired product 7b was obtained in a 69% yield when 1.8 equivalents of KHMDS was used. Scheme 2 To define the scope and limitations of the present method, we prepared ortho-, meta-, and para-methylor chloro-substituted N-benzylic salts 4c 4k and used them to obtain various types of N-cyano- -arylpipecolinic acid derivatives (Table 1). In most cases, the S H rearrangement of 4 and following the von Broun reaction of 5 proceeded, giving reasonable yields (entries 1 9, 1st and 2nd step). One exception was the ring-opening reaction of 2,4-dimethylphenyl derivative 5g, which resulted in a low yield of 6g (20%) because of a competing -bromo substitution reaction 9 (R 3 = Me, entry 5, 2nd step). The cyclization of isopropyl or tert-butyl ester-derived substrates 6c 6j proceeded smoothly to give 7c 7j in the presence of 1.1 equivalents of KHMDS (entries 1 8, 3rd step). The amide derivative 6k did not cyclize at all because of the poorer reactivity of the amide enolate (entry 9, 3rd step). Next, we applied this method to the preparation of an -benzylpipecolinic acid ester, 7d, and a seven-membered cyclic -amino acid ester, 7l, via a base-induced [1,2] Stevens rearrangement 5 (Scheme 3). When the reaction of 4d and 4l was carried out in dichloromethane using sodium tert-butoxide as a base, the [1,2] Stevens rearrangement proceeded preferably to afford -benzylated 5d and 5l. 10 Procedures similar to those described in Table 1 gave the desired products 7d and 7l, respectively. Finally, we attempted to remove the N-cyano substituent, as in 7d, to obtain N-free -substituted pipecolinic acid ester 9d (Scheme 4). The hydrogenation of 7d under a hydrogen atmosphere afforded the corresponding amidine 8d in a 93% yield. Treatment of 8d with sodium borohydride gave the desired secondary amine 9d in a 75% yield with a side product of N-methyl derivative 2.

4 Table 1 Preparation of various types of -aryl pipecolinic acid derivatives 7 from 4 Entry R 1 R 2 R 3 R 4 1st Step: 5 (%) a 2nd Step: 6 (%) a 3rd Step: 7 (%) a,b 1 Oi-Pr H H H c Ot-Bu H H H d Ot-Bu Me H H e Ot-Bu Cl H H f Ot-Bu H Me H g c 84 6 Ot-Bu H Cl H h Ot-Bu H H Me i Ot-Bu H H Cl j NEt2 H H H k a Isolated yields. b Reactions were carried out in the presence of 1.1 equivalents of KHMDS. c tert-butyl 2-bromo-2-(2,4-dimethylphenyl)acetate prepared by -bromo-substitution was obtained as a main product. Scheme 3 Scheme 4 In conclusion, we have developed a new synthetic method for the preparation of N-cyano- -aryl pipecolinic acid esters 7 from tetraalkylammonium salts 4 via rearrangement (Sommelet Hauser or [1,2]

5 Stevens), the von Broun reaction, and intramolecular -alkylation. The N-cyano substituent, as in 7, can be removed via hydrogenation and hydride reduction. The method presented herein is a unique and simple preparative method for -aryl pipecolinic acid esters. 11 EXPERIMENTAL Infrared spectra were recorded on a Perkin Elmer Spectrum GX FT-IR spectrometer. 1 H and 13 C NMR spectra were measured on a Varian 400 MHz spectrometer ( 1 H: 400 MHz, 13 C: 100 MHz) and a 700 MHz spectrometer ( 1 H: 700 MHz, 13 C: 175 MHz). The splitting patterns are denoted as follows: s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; and br, broad peak. High-resolution mass spectra were measured on a Thermo Fisher Scientific LC/FT-MS spectrometer. Reactions involving air- or moisture-sensitive compounds were conducted in appropriate round-bottomed flasks with a magnetic stirring bars under an argon atmosphere. Tetrahydrofuran (THF) was purchased from KANTO Chemical Co., Inc., Japan as an anhydrous solvent. Cyanogen bromide was purchased from KANTO Chemical Co., Inc., Japan. A 0.5 M potassium bis(trimethylsilyl)amide (KHMDS) solution in toluene and a 1.0 M potassium tert-butoxide solution in THF were purchased from Tokyo Chemical Industry Co., Ltd (TCI). For thin layer chromatography (TLC) analysis throughout this work, Merck TLC plates (silica gel 60 F254), or Fuji Silysia Chemical TLC plates (NH, Fuji Silysia Chemical Ltd., Japan) for amidine 8d were used. The products were purified by preparative column chromatography on silica gel (silica gel 60N, spherical neutral, KANTO Chemical Co., Inc., Japan) or ph-controlled silica gel (Chromatorex NH DM1020, Fuji Silysia Chemical Ltd., Japan) for amidine 8d. Representative procedure for the preparation of tert-butyl 2-(pyrrolidin-1-yl)-2-(o-tolyl)acetate (5d). A 1.0 M THF solution of potassium tert-butoxide (4.9 ml, 4.9 mmol) was added to a solution of 4d (1.58 g, 4.43 mmol) in THF (44 ml) at 0 C. The mixture was stirred for 4 h at the same temperature under an argon atmosphere. The resulting mixture was quenched with saturated aqueous ammonium chloride and extracted with ethyl acetate. The combined extracts were washed with saturated aqueous sodium hydrogen carbonate and brine. The solution was dried over sodium sulfate and concentrated. Purification of the residue by chromatography on silica gel (hexane/ethyl acetate = 5/1 to 2/1 as the eluent) gave 5d (1.00 g, 82% yield) as a colorless oil; IR (film) 3051, 2972, 2874, 2785, 2722, 1741, 1603, 1483, 1459, 1391, 1367, 1334, 1253, 1214, 1146, 1038, 977, 940, 906, 845, 815, 751 cm -1 ; 1 H NMR (400 MHz, CDCl3) 7.61 (1H, dd, J = 7.4, 1.2 Hz, ArH), (3H, m, ArH), 4.12 (1H, s, CHCO), (2H, m, NCH2), (2H, m, NCH2), 2.43 (3H, s, ArCH3), (4H, m, CH2), 1.36 (9H, s, t-bu); 13 C NMR (100 MHz, CDCl3) 170.9, 136.3, 135.9, 130.0, 128.0, 127.1, 125.9, 80.5, 69.5, 52.0, 27.7, 23.3, 19.6; HRMS ESI (m/z): [M+H] + calcd for C17H26NO2: Found:

6 Representative procedure for the preparation of tert-butyl 2-(N-(4-bromobutyl)cyanamido)-2- (o-tolyl)acetate (6d). A solution of cyanogen bromide (95%, 1.22 g, 11 mmol) in dichloromethane (2 ml) was added to a solution of 5d (1.00 g, 3.63 mmol) in dichloromethane (18 ml) at room temperature under an argon atmosphere and the solution was stirred for 1 h. The resulting solution was treated with saturated aqueous sodium hydrogen carbonate and extracted with ethyl acetate. The combined extracts were washed with saturated aqueous sodium bromide, dried over sodium sulfate, and concentrated by evaporation. Purification of the residue by chromatography on silica gel (hexane/ethyl acetate = 5/1 to 1/1 as the eluent) afforded 6d (1.23 g, 89% yield) as a white solid; IR (film) 3067, 2977, 2935, 2880, 2212, 1738, 1605, 1491, 1460, 1393, 1369, 1342, 1255, 1221, 1155, 1074, 1041, 955, 881, 861, 826, 754 cm -1 ; 1 H NMR (400 MHz, CDCl3) (4H, m, ArH), 4.84 (1H, s, CHCO), 3.37 (1H, dt, J = 12.6, 6.4 Hz, CH2), 3.35 (1H, dt, J = 12.6, 6.4 Hz, CH2), 3.10 (2H, t, J = 6.8 Hz, CH2), 2.42 (3H, s, ArCH3), (4H, m, CH2), 1.50 (9H, s, t-bu); 13 C NMR (100 MHz, CDCl3) 168.6, 137.5, 131.3, 131.1, 129.6, 128.0, 126.4, 115.6, 83.4, 64.1, 49.6, 32.6, 29.4, 27.9, 26.3, 19.3; HRMS ESI (m/z): [M+Na] + calcd for C18H25N2O2BrNa: Found: Representative procedure for the preparation of tert-butyl 1-cyano-2-(o-tolyl)piperidine-2- carboxylate (7d). A solution of 6d (0.61 g, 1.6 mmol) in THF (8.1 ml) was cooled at 78 C and treated with a 0.5 M KHMDS solution in toluene (3.6 ml, 1.8 mmol). The solution was stirred for 1 h at the same temperature and allowed to warm to room temperature. After stirring for 15 h for room temperature, the resulting mixture was quenched with saturated aqueous ammonium chloride and extracted with ethyl acetate. The combined extracts were washed with brine, dried over sodium sulfate, and concentrated. The residue was purified by chromatography on silica gel to obtain 7d (0.42 g, 87% yield) as a white solid; IR (film) 3061, 2964, 2928, 2862, 2210, 1730, 1454, 1392, 1367, 1332, 1286, 1250, 1143, 1112, 1085, 1060, 1006, 971, 944, 865, 837, 755, 746, 729 cm -1 ; 1 H NMR (400 MHz, CDCl3) (4H, m, ArH), (2H, m, NCH2), 2.62 (3H, s, ArCH3), 2.40 (1H, ddd, J = 13.6, 3.6, 3.6 Hz, CH2), 2.13 (1H, ddd, J = 13.6, 13.6, 3.6 Hz, CH2), (1H, m, CH2), (2H, m, CH2), (1H, m, CH2), 1.55 (9H, s, t-bu); 13 C NMR (100 MHz, CDCl3) 169.5, 137.0, 136.0, 133.2, 128.7, 127.2, 126.0, 117.0, 83.4, 70.6, 49.4, 32.0, 27.9, 23.5, 21.2, 20.9; HRMS ESI (m/z): [M+Na] + calcd for C18H24N2O2Na: Found: Preparation of tert-butyl 1-(iminomethyl)-2-(o-tolyl)piperidine-2-carboxylate (8d). A mixture of 7d (153 mg, mmol) and palladium on activated carbon (loading: 10 wt.%, 29 mg) in methanol (5 ml) was stirred for 1 h at room temperature under a hydrogen atmosphere. The resulting mixture was filtered through a pad of Celite and the filtrate was concentrated. The residue was purified by chromatography on ph-controlled silica gel (Chromatorex NH DM1020)(hexane/ethyl acetate = 3/1 to

7 2/1 as the eluent) to obtain 8d (143 mg, 93% yield) as a white solid; IR (KBr) 3427, 3287, 3057, 2978, 2947, 2869, 2822, 1725, 1620, 1454, 1392, 1356, 1285, 1244, 1150, 1125, 1005, 973, 956, 897, 845, 820, 778, 756, 723 cm -1 ; 1 H NMR (400 MHz, CDCl3) 7.57 (1H, s, CH=N), (3H, m, ArH), 7.08 (1H, dd, J = 8.2, 1.2 Hz, ArH), (1H, m, NH), (1H, m, NCH2), 2.50 (3H, s, ArCH3), (1H, m, NCH2), 2.00 (1H, ddd, J = 13.3, 13.3, 3.8 Hz, CH2), (2H, m, CH2), (2H, m, CH2), 1.54 (9H, s, t-bu); 13 C NMR (100 MHz, CDCl3) 171.2, 161.3, 138.5, 136.0, 133.3, 127.7, 127.3, 126.1, 82.7, 71.9, 40.3, 33.3, 27.9, 23.3, 22.0, 21.7; HRMS ESI (m/z): [M+H] + calcd for C18H27N2O2: Found: Preparation of tert-butyl 2-(o-tolyl)piperidine-2-carboxylate (9d) and tert-butyl 1-methyl-2-(o-tolyl)piperidine-2-carboxylate (2). Sodium borohydride (32 mg, 0.85 mmol) was added to a solution of 8d (45.8 mg, mmol) in THF (1.35 ml) and water (0.15 ml) at 0 C. After stirring for 1 h at room temperature, the resulting mixture was diluted with water and extracted with ethyl acetate. The combined extracts were washed with brine, dried over sodium sulfate, and concentrated. The residue was purified by chromatography on silica gel (hexane/ethyl acetate = 15/1 to 10/1 as the eluent) to obtain 9d (31.3 mg, 75%) as a colorless oil and 2 (2.4 mg, 5% yield) as a colorless oil. 9d: colorless oil; IR (film) 3427, 3333, 3059, 2932, 2867, 2827, 2783, 2690, 1724, 1601, 1479, 1453, 1391, 1366, 1239, 1161, 1121, 1059, 1030, 969, 930, 898, 838, 755 cm -1 ; 1 H NMR (400 MHz, CDCl3) (1H, m, ArH), (3H, m, ArH), 2.89 (1H, dddd, J = 12.2, 4.5, 4.5, 0.8 Hz, NCH2), 2.82 (1H, ddd, J = 12.2, 9.5, 3.6 Hz, NCH2), 2.47 (3H, s, ArCH3), (1H, m, CH2), 2.18 (1H, br, NH), (3H, m, CH2), (2H, m, CH2), 1.44 (9H, s, t-bu); 13 C NMR (100 MHz, CDCl3) 174.5, 142.0, 136.0, 132.2, 126.8, 126.2, 125.6, 80.9, 65.7, 42.7, 32.9, 27.9, 25.4, 21.7, 21.0; HRMS ESI (m/z): [M+H] + calcd for C17H26NO2: Found: : colorless oil; IR (film) 3059, 2974, 2928, 2804, 2719, 1716, 1477, 1453, 1391, 1366, 1291, 1238, 1212, 1158, 1135, 1099, 1056, 1033, 1004, 956, 894, 847, 773, 754, 722 cm -1 ; 1 H NMR (400 MHz, CDCl3) 7.30 (1H, br, ArH), (3H, m, ArH), 2.79 (1H, d, J = 11.2 Hz, NCH2), 2.66 (1H, dd, J = 11.2, 11.2 Hz, NCH2), 2.55 (3H, br, ArCH3), 2.30 (3H, s, NCH3), 2.16 (1H, d, J = 11.2 Hz, CH2), (5H, m, CH2), 1.55 (9H, s, t-bu); 13 C NMR (100 MHz, CDCl3) 171.9, 141.7, 136.6, 132.4, 127.1, 126.5, 125.4, 81.2, 72.3, 50.8, 40.9, 34.5, 28.4, 25.4, 22.1, 21.0; HRMS ESI (m/z): [M+H] + calcd for C18H28NO2: Found: ACKNOWLEDGEMENTS This work was supported by KAKENHI (Grant-in-Aid for Young Scientists (B), ), The Union Tool Scholarship Foundation, The Foundation for Japanese Chemical Research, and The Uchida Energy Science Promotion Foundation.

8 REFERENCES AND NOTES 1. For reviews: C. Cativiela and M. Ordóñez, Tetrahedron: Asym., 2009, 20, 1; K.-H. Park and M. J. Kurth, Tetrahedron, 2002, 58, 8629; C. Cativiela and M. D. Díaz-de-Villegas, Tetrahedron: Asym., 2000, 11, D.-R. Hou, S.-Y. Hung, and C.-C. Hu, Tetrahedron: Asym., 2005, 16, 3858; S. N. Osipov, C. Bruneau, M. Picquet, A. F. Kolomiets, and P. H. Dixneuf, Chem. Commun., 1998, 2053; Y. Matsumura, T. Kinoshita, Y. Yanagihara, N. Kanemoto, and M. Watanabe, Tetrahedron Lett., 1996, 37, 8395; J.-F. Berrien, J. Royer, and H.-P. Husson, J. Org. Chem., 1994, 59, J. Pachot and C. Dini, PCT Int. Appl. WO , 2011; J. S. Dickstein, M. W. Fennie, A. L. Norman, B. J. Paulose, and M. C. Kozlowski, J. Am. Chem. Soc., 2008, 130, 15794; H. Yasuo, M. Suzuki, and N. Yoneda, Chem. Pharm. Bull., 1979, 27, V. G. Nenajdenko, A. V. Gulevich, and E. S. Balenkova, Tetrahedron, 2006, 62, For reviews: J. B. Sweeney, Chem. Soc. Rev., 2009, 38, 1027; Nitrogen, Oxygen, and Sulfur Ylide Chemistry, ed. by J. S. Clark, Oxford University Press, Oxford, 2002; I. E. Markó, Comprehensive Organic Synthesis, Vol. 3, Chap. 3.10, ed. by B. M. Trost and I. Fleming, Pergamon, Oxford, E. Tayama, K. Takedachi, H. Iwamoto, and E. Hasegawa, Tetrahedron, 2010, 66, 9389; E. Tayama, K. Orihara, and H. Kimura, Org. Biomol. Chem., 2008, 6, 3673; E. Tayama and H. Kimura, Angew. Chem. Int. Ed., 2007, 46, Even if the reaction was carried out at 40 C for 15 h, the almost same results were obtained. 8. For a review: J. H. Cooley and E. J. Evain, Synthesis, 1989, E. Tayama, R. Sato, K. Takedachi, H. Iwamoto, and E. Hasegawa, Tetrahedron, 2012, 68, The Sommelet Hauser and [1,2] Stevens rearrangement are competitive. The selectivity of these rearrangements is determined by the base, solvent, temperature, and the structure of the substrate. For an example, the use of a sodium base (sodium tert-butoxide) and a nonpolar solvent (dichloromethane) preferred to give the [1,2] Stevens rearrangement product. Other examples: see, ref We attempted the reactions of 2-methyl- and 3-methoxy-pyrrolidinyl derivatives to obtain the corresponding substituted pipecolinic acid esters. However, the reactions were unsuccessful because of the formation of a mixture of four isomers after von Broun reaction.